Multifetal Pregnancy After Implementation of a Publicly Funded Fertility Program

Key Points Question What is the association between a publicly funded fertility program and multifetal pregnancy? Findings In this population-based cohort study of 1 724 899 pregnancies in Ontario, Canada, the multifetal pregnancy rate was 1.4% in unassisted conception, 10.5% after ovulation induction or intrauterine insemination (OI/IUI), and 15.5% after in vitro fertilization (IVF). A comparison of the era before elective single embryo transfer (eSET) was promoted (ie, 2006-2011) with the era after the introduction of an eSET mandate (ie, 2016-2021) revealed that the multifetal pregnancy rate decreased from 12.9% to 9.1% after OI/IUI and from 29.4% to 7.1% after IVF. Meaning These findings suggest that publicly funded IVF programs mandating eSET are associated with a decrease in multifetal pregnancy rates; however, additional strategies are needed to decrease multifetal pregnancy, especially after OI/IUI.


Introduction
Infertility-the inability to conceive after 1 year of unprotected intercourse-affects 1 in 6 couples globally. 1Advances in fertility treatments have benefited many of those who otherwise would not be able to conceive but have also led to disproportionately high rates of multifetal pregnancies. 24][5][6][7][8] Approximately 1% to 2% of all live births in Canada are achieved using fertility treatment. 6From 2005 to 2014, Ontario historically had the highest multifetal pregnancy rate in Canada of 3.6% per 100 births. 9en oral medications are used for ovulation induction or intrauterine insemination (OI/IUI), the rate of a multifetal pregnancy is 3% to 13% 10,11 ; with injectable gonadotropins preceding IUI, that rate increases to approximately 30%. 2,10In the US in 2011, approximately 19% of twin pregnancies were attributable to OI or ovarian stimulation/IUI, whereas for higher-order multiple pregnancies, that proportion was 45%. 2 Moreover, the estimated proportion of twins after in vitro fertilization (IVF) was 17%, whereas the proportion of higher-order multiple pregnancies was 32%. 2 In the early years of IVF, it was common to transfer 2 or more embryos to increase the likelihood of a pregnancy, but this resulted in multifetal pregnancy rates as high as 30%. 124][15] Given that eSET offers a safe and effective alternative to multiple embryo transfer, 16,17 publicly funded assisted reproductive therapy (ART) programs have adopted an eSET policy, with some variations.For example, in Australia, eSET is not a mandatory practice but strongly recommended. 180][21][22][23] In Canada, the province of Quebec adopted a mandatory eSET policy in 2010, with some exceptions.In its first full year, there was a 60% relative decrease in the rate of multifetal pregnancies. 24Ontario's publicly funded program, which offers an unlimited number of IUI cycles and 1 cycle of IVF for individuals younger than 43 years, mandated eSET starting in December 2015. 25 contrast to IVF, preventing a multifetal pregnancy is more challenging after OI/IUI, given the unpredictable number of follicles that may be stimulated. 26Hence, OI/IUI has been more difficult to regulate.Furthermore, prior epidemiologic studies of fertility treatment and multifetal pregnancy only assessed fetuses at birth, while not accounting for potential fetal reductions that may have been performed earlier in pregnancy. 27Accordingly, this population-based cohort study was undertaken to evaluate the association between fertility treatment and multifetal pregnancy rates in Ontario, while accounting for both fetal reductions and all births.

Methods
This retrospective, population-based cohort study was conducted using existing linked administrative health data from Ontario, Canada (eTable 1 in Supplement 1).Data were linked using unique maternal and child identifiers and analyzed at ICES, an independent, nonprofit research institute whose legal status under Ontario's health information privacy law allows it to collect and analyze health care and demographic data, without consent, for health system evaluation and improvement.The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline and was reviewed for ethical compliance by the Queen's University Health Sciences & Affiliated Teaching Hospitals Research Ethics Board.

Data Sources and Study Cohort Creation
This study comprised all live births and stillbirths in Ontario occurring at 20 weeks' gestation or later, as well as fetal reductions, among pregnant women aged 18 to 50 years between April 1, 2006, and  March 31, 2021.The study was restricted to individuals with valid Ontario Health Insurance Program (OHIP) coverage within 2 years before the estimated date of conception, which is most Ontarian residents.Data on race and ethnicity were not available in the study data sets.
Data were analyzed through ICES, an independent, nonprofit research institute funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care.As a prescribed entity under Ontario's privacy legislation, ICES is authorized to collect and use health care data for the purposes of health system analysis, evaluation, and decision support.Secure access to these data is governed by policies and procedures that are approved by the Information and Privacy Commissioner of Ontario.Information on births and fertility treatment were accessed from the Better Outcomes Registry & Network (BORN) Ontario and Niday Legacy data sets (2006-2021).The BORN Ontario database captures 99% of maternal and newborn health records. 28The ICES data sets have been validated for sociodemographic characteristics, physician billing claims, and primary hospital diagnoses. 29Fetal reductions were obtained using the ICES-derived MOMBABY data set and OHIP billing codes, which are listed in eTable 2 in Supplement 1.

Exposure Status and Outcomes
The exposure of interest was mode of conception, categorized as follows: (1) unassisted conception (reference group), (2) OI/IUI, and (3) IVF.The primary outcome of interest was a multifetal pregnancy, namely, a twin (ie, 2 fetuses) or a higher-order (ie, Ն3 fetuses) pregnancy.Those who had a multifetal reduction to a singleton pregnancy were considered originally as twins, and those who had a multifetal reduction to a twin or more were considered as higher-order multiple pregnancies. 27

Covariates
We adjusted for potential factors that might confound the association between mode of conception and multifetal pregnancy, including maternal age at delivery, parity, income quintile, immigration status (immigrant or born in Canada), 30 obesity, prepregnancy diabetes, and chronic hypertension.
Obesity was defined as a maternal body mass index of 30 or greater (calculated as weight in kilograms divided by height in meters squared) or, when body mass index was not known, based on an OHIP billing code for obesity (International Classification of Diseases, Ninth Revision [ICD-9] code 278) within the 2-year period before the estimated date of conception.

Statistical Analysis
The proportion of multifetal pregnancies by mode of conception was calculated overall and stratified by era (fiscal years April 2006 to March 2011, April 2011 to March 2016, and April 2016 to March 2021).Modified Poisson regression, with robust error variance, generated adjusted relative risks (ARRs) and 95% CIs, accounting for potentially more than 1 pregnancy in the same mother during the study period.Population attributable fractions (PAFs) were calculated as an estimate of the proportion of multifetal pregnancies in the total population that might be attributed to each type of fertility treatment.The PAF formula was as follows: PAF = 100 × Pd × (ARR − 1)/ARR), where Pd is the proportion of cases exposed to risk factor. 31Finally, absolute rate differences (ARDs) compared the era before eSET was promoted (ie, 2006-2011) to the era after the introduction of the eSET mandate (ie, 2016-2021).
Additional analysis 1 further assessed known maternal sociodemographic characteristics and preexistent health conditions and the associated risk of multifetal pregnancy.Additional analysis 2 assessed mode of conception and the risk of multifetal pregnancy reduction, as well as preterm birth.
Statistical significance was set at a 2-sided P < .05.All statistical analyses were performed using SAS, version 9.4 for UNIX (SAS Institute Inc).

Results
Of all 1 724 899 pregnancies, 1 670 825 (96.9%) were by unassisted conception, 24 395 (1.4%) by OI/IUI, and 29 679 (1.7%) by IVF (eFigure in Supplement 1).The mean (SD) maternal age was 30.6 (5.2) years among women with unassisted conception, 33.1 (4.4) years in those with OI/IUI, and 35.8 (4.7) years in those with IVF.A greater proportion of individuals who received fertility treatment by OI/IUI or IVF tended to be older, reside in a high-income quintile neighborhood, or have preexisting health conditions, including obesity, diabetes, and chronic hypertension, in contrast to women who had unassisted conception (Table 1).
In additional analysis 1, risk factors for multifetal pregnancy are shown in eTable 3 in Supplement 1.In additional analysis 2, mode of conception was significantly associated with a higher risk of multifetal pregnancy reduction, as well as preterm birth (eTable 4 in Supplement 1).

Discussion
In this cohort of 1.7 million pregnancies, OI/IUI and IVF were both associated with multifetal pregnancies.Although there was a decrease in the overall rate of multifetal pregnancies between 2006 and 2021, that decrease was more substantial for IVF pregnancies than for those conceived after OI/IUI.Society. 32This recommendation was paralleled by a significant decrease in multifetal pregnancy rates in the neighboring province of Quebec after public funding for IVF was introduced in 2010. 24[20][21][22][23][24] The Ontario Fertility Program funds 1 cycle of IVF.Some patients decide to do a private cycle either instead of waiting for the publicly funded cycle or after a failed publicly funded IVF cycle.The Canadian Assisted Reproductive Technology Registry reported 66 994 IVF cycles in Ontario between 2016 and 2021 in Ontario. 33Of these, 50% were publicly funded and 50% were private.The respective pregnancy rates were 37.8% and 41.4%, and the respective multifetal live birth rates were 0.9% and 2.1%.Certainly, future studies should address the cost-effectiveness of providing 1 vs multiple publicly funded IVF cycles, 24 especially, because some couples in Ontario still pursue privately paid IVF cycles, 33 which can result in a higher rate of multifetal pregnancy and an inherently higher risk of maternal and neonatal morbidity. 3,27provements and advances in ART have also contributed to the success of eSET programs.
Advances in embryo culture media have led to a shift in IVF practice from cleavage-stage embryo transfer to blastocyst-stage embryo transfer, resulting in higher live birth rates. 34Embryo cryopreservation has also been a key to implementing eSET programs because this allows the elective freezing of all available embryos, with subsequent single frozen blastocyst transfer, resulting in higher cumulative pregnancy rates. 35though the Ontario Fertility Program mandated eSET for women undergoing public IVF, no equivalent requirement was made for OI/IUI.Even so, the multifetal pregnancy rate after OI/IUI decreased from 12.9% in 2006 to 2011, to 10.7% in 2011 to 2016, and to 9.1% in 2016 to 2021.Hence, it is possible that the introduction in 2015 of public IVF funding might have contributed to this slight decrease in multifetal pregnancy after OI/IUI, because some couples might have chosen to move to IVF after a few cycles of IUI had failed or as their first-line treatment.
For OI/IUI, practice recommendations have suggested using less potent ovarian stimulation therapies and cancellation of IUI cycles when the ovarian response suggests a high risk of a multifetal pregnancy. 36,37Choosing the right type of OI medication is important.For women with polycystic ovary syndrome, for example, OI using oral letrozole results in higher live birth rates than with oral clomiphene citrate without increasing multifetal pregnancy. 37In women with polycystic ovary syndrome who do not achieve a pregnancy with letrozole, injectable low-dose gonadotropins may be used as a second-line agent in OI/IUI, with careful monitoring of follicle count using ultrasonography. 37r couples with unexplained infertility and who undergo IUI, ovarian stimulation with oral clomiphene citrate or letrozole is recommended. 38Given the risk of multiple pregnancy, the use of injectable gonadotropins is generally not recommended in this context. 37,38In Canada, however, injectable gonadotropins are sometimes offered, with patients made aware that this regimen is associated with a higher multifetal pregnancy rate per cycle than IUI with oral agents. 39Controlled ovarian stimulation and IUI, with strict cancellation criteria, result in similar pregnancy and multifetal pregnancy rates compared with eSET or modified natural IVF. 40

Strengths and Limitations
Strengths of this study include the use a large population-based sample from a validated provincial registry, 41 comprising all births within a publicly funded health care system.The ability to account for fetal reductions and to study not only IVF but also OI/IUI are each novel study strengths.
This study also has some limitations.Nondifferential misclassification of the study exposure was unlikely, but some individuals in the unassisted conception group may have used an oral medication

Figure .
Figure.Rates of Multifetal Pregnancy by Mode of Conception and Year of the Pregnancy 35 30 25 20 15 10 5 0

Table 1 .
Participant Characteristics by Mode of Pregnancy Conception From 1 724 899 Live Births and Stillbirths in Ontario, Canada, April 1, 2006, to March 31, 2021 a a Data are presented as number (percentage) of participants unless otherwise indicated.

Table 2 .
Association Between Mode of Conception and Risk of Any Multifetal Pregnancy a Adjusted for maternal age at delivery, income quintile, immigration status, obesity, parity, prepregnancy diabetes, and chronic hypertension.

Table 3 .
Association Between Mode of Conception and Risk of a Twin Pregnancy a Adjusted for maternal age at delivery, income quintile, immigration status, obesity, parity, prepregnancy diabetes, and chronic hypertension.